A Mouse Model of Shiftwork Reveals Sex-Specific Impairments in Circadian Behavior and Reproductive Tissue Timekeeping

Abstract Approximately 21 million Americans are employed in nighttime or rotating shiftwork, which is linked with numerous health risks, including reduced reproductive success. While there is a strong body of clinical evidence associating shift workers with deficits in fertility, very little is known about the mechanisms by which shiftwork produces reproductive dysfunction. One important feature of shiftwork is extensive exposure to light at night. Light is one of the strongest timing cues for the circadian system, where exposure to mistimed light (light at night) can disrupt timekeeping throughout the body, leading to a mistiming of physiological processes and resulting in disease development. Our goal is to determine if a light-based model of rotating shiftwork (shift-light), composed of an alternating 6 hour phase advance or delay every 4 days for 5-10 weeks, disrupts circadian rhythms in the reproductive hypothalamic-pituitary-gonadal (HPG) axis, leading to mis-timed tissue rhythms and reduced fertility. We hypothesize that shift-light disrupts wheel running behavior and underlying cellular circadian rhythms in the HPG axis, resulting in reduced reproductive function. Using the validated circadian Per2:luciferase reporter mice, we assessed wheel-running behavior and Per2:luciferase rhythms in tissue explants from males and females. Behavioral data revealed that both sexes adapt their wheel running to shift-light paradigm; however, females, but not males, displayed a significant deficit in their ability to entrain to phase advances following 4 shifts. This sex-specific disruption was supported by preliminary tissue explant Per2:luciferase rhythms, which suggest that shift-light alters tissue level circadian phase synchrony in female, but not male, HPG axis tissues. Importantly, females exhibited shortened estrous cycling during shift-light, suggesting the altered HPG axis synchrony could be directly impacting reproductive function. We are currently working to extend this work to determine how this desynchrony impacts hormone release, including luteinizing hormone and follicle stimulating hormone. Together, this work provides insight into how shiftwork may influence circadian rhythms in reproductive tissues and suggests that females may have increased vulnerability to reproductive deficits from shiftwork.